Proposed research is directed toward an understanding of the mechanisms of operation of three systems which contribute to hemostasis: The development of fibrin clot structure, the conversion of prothrombin into thrombin and the maintenance of platelet response and structural and metabolic integrity. Our objective is to develop each to the point where combination becomes possible, with the purpose of deriving functional interrelationships. (1) The development of fibrin clot structure involves, first, an enzymatic conversion by thrombin of fibrinogen into monomer fibrin. With fibrinogen in excess, monomer fibrin is stabilized by interaction and kept in solution. When stabilizing capacity is exceeded, monomer fibrins engage in a set of pzogressively cooperative association reactions which lead to a fibrin network. Our objective is to specify reactions more quantitatively and to determine the particular effects on the reaction sequence produced by physiologically active agents such as certain of the fibrinogen/fibrin degradation products. (2) The step at which prothrombin is converted to thrombin, in the intrinsic or extrinsic systems, involves concerted interactions of prothrombin, calcium ion, F-V and F-Xa at loci on colloidal lipoprotein particles. Loci on tissue factor appear to be controlled so that converting activity develops at nearly the same time for most viable loci. Our objective is to determine the organization of converting loci, the molecular mechanism of conversion and the mechanism by which activation of loci is controlled. (3) Platelt metabolic activity and interaction with environmental components control response to perturbation and the maintenance of structural and metabolic integrity. Fibrinogen appears mainly to be involved in the expression of ADP-induced aggregation response and plasma cofactor in the maintenance of integrity. Our objective is to develop procedures to reduce the effects of platelet-gel matrix contact to allow a more definitive examination of inherent characteristics.